Peptide macrocycles

Macrocyclic peptides and depsipeptides ( macrocyciic peptides with amide and ester linkages) are important natural compounds. They have been synthesized in low yield from open-chain precursors by DCC treatment at high dilution (E. SchrSder, 1963 M.M. Shemyakin,... 

Macrocyclic peptides as antibacterial glycopeptide antibiotics 98KGS1605. 

Investigation of immune recognition segments in presynapsis and postsynapsis neurotoxins (macrocyclic peptides) 98KPS22. 

Structural determination of macrocyclic peptides cyclosporins by mass spectrometry 97CLY2. 

The macrocyclization of a peptide was carried out by nucleophihc substitution on a fluorobenzene by the sulfide group of the terminal cysteine of a pentapeptide [164]. The peptide 261 was prepared by standard SPPS and was cyclized under microwave irradiation at 50 °C for 10 min in DMF (Scheme 96). The yields of 262, after cleavage with TFA, were remarkably high for a macrocyclic peptide (70%) and also the resulting HPLC purity was very high. 

TE-catalyzed cyclization is not limited to the synthesis of macrocyclic peptides by catalyzing the formation of aC N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a di-domain excised from fengycin synthase was... 

The group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

Scheme 7.32 Microwave-mediated thioalkylation to prepare precursors for macrocyclic peptide synthesis.

Recent studies by Grubbs on the effect of stereochemistry on synthesis of macrocyclic peptides (disubstituted alkenes) by ring closing metathesis were not disclosed at the time of our planning. See (a) Ref. 6a. (b) Miller SJ, Blackwell H, Grubbs RH (1996) J Am Chem Soc 118 9606... 

In a number of laboratories macrocyclic peptides have been studied as enzyme models 47,63, 70, 72a, 91). A bicyclic peptide (17) with considerable apolar character was made by Murakami et al. (70) in which Hex is 6-amino-hexanoyl Und is co-aminoundecanoyl. The esterolysis of p-nitrophenyl carboxylates by (17) was studied over the pH range 10-12. The rate depends on the ionization of one group (pK 12.3), which is apparently the anionic imidazole group. 

The energetics of peptide-porphyrin interactions and peptide ligand-metal binding have also been observed in another self-assembly system constructed by Huffman et al. (125). Using monomeric helices binding to iron(III) coproporphyrin I, a fourfold symmetric tetracarboxylate porphyrin, these authors demonstrate a correlation between the hydropho-bicity of the peptide and the affinity for heme as well as the reduction potential of the encapsulated ferric ion, as shown in Fig. 12. These data clearly demonstrate that heme macrocycle-peptide hydrophobic interactions are important for both the stability of ferric heme proteins and the resultant electrochemistry. 

For biosynthetic studies of the formation of the macrocyclic peptide antibiotic thiostrepton, isotopically labeled [ C]-AAs were employed. The quinaldic acid moiety 97 of this antibiotic was shown to be biosynthesized from 3-methyltryptophan, and a mechanism has been proposed (93JA7992). 

Substitution of the terminal amine with ligating groups, such as catecholate, hydrox-amate or diketonate, lead to the formation of A-cis chiral complexes. In these structures the chiral information content is located in the amino acid bridges, instead of the macrocyclic peptide ring structure used in ferrichrome. It should be emphasized... 

Electrochemical studies (62, 64,106,137) have shown that nickel(III) complexes with macrocycles, peptides, and diimine ligands are rel-... 

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

Phan, J., Shi, Z-D., Burke, T.R., Jr., and Waugh, D.S. (2005) Crsytal structures of a high-affinity macrocyclic peptide mimetic complex with the Grb2 SH2 domain. J.Mol. Biol. 353,104-115. 

Another group at Boehringer Ingelheim has used RCM to prepare macrocyclic peptides active against the hepatitis C virus.37 39 The metathesis reactions were used to form 15-membered rings and the trans-alkene (Schemes 28.7 and 28.8). The length of the sidechains determined the position of the unsaturation in the macrocycle. 

While protein kinases are responsible for the phosphorylation of their substrates, protein phosphatases perform the opposite duty, removing phosphate groups from their substrates, thus countering the functional impact of the kinases. The two major types of protein phosphatases are the serine/threonine phosphatases and tyrosine phosphatases. Several natural compounds with potent serine/threonine phosphatase inhibitory activity have been identified, including the cyanobacterial metabolite microcystin [105,106]. This compound labels its targets via a Michael addition of a noncatalytic active site cysteine residue with an acceptor in the macrocyclic peptide backbone [107]. A fluorescent probe based on microcystin was synthesized by Shreder et al., and its use in Jurkat lysates identified two previously undescribed phosphatase targets of microcystin, PP-4 and PP-5 [108]. Whereas serine/threonine... 

Two important examples of cyclic peptides will be highlighted in which amino acid sequences of larger proteins have been successfully used as part of macrocyclic peptide structures to mimic in an almost pars pro toto approach important properties of the parent protein. 

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